Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A (original) (raw)
Related papers
Haemophilia, 2016
Introduction: Primary factor VIII (FVIII) prophylaxis is the optimal treatment in children with severe haemophilia A. They are expected to benefit from extended half-life (T 1/2) FVIII coverage by reduced infusion frequency while maintaining haemostatic efficacy. Aims: To determine immunogenicity, pharmacokinetics (PK), efficacy, safety and quality of life of prophylaxis with a polyethylene glycol (peg)-ylated FVIII (BAX 855) based on full-length recombinant FVIII (ADVATE) in paediatric previously treated patients (PTPs) with severe haemophilia A. Methods: PTPs <12 years without history of FVIII inhibitors received twice-weekly infusions of 50 AE 10 IU kg À1 BAX 855 for ≥50 exposure days. Prophylactic dose increases to ≤80 IU kg À1 were allowed under predefined conditions. PK was evaluated after single infusions of 60 AE 5 IU kg À1. Results: T 1/2 and mean residence time were extended 1.3-to 1.5-fold compared to ADVATE (n = 31), depending on the analysis used. The point estimate for the mean annualized bleeding rate in 66 subjects receiving a median of 1.9 weekly infusions of 51.3 IU kg À1 of BAX 855 each was 3.04 (median 2.0); 1.10 (median 0) for joint and 1.16 (median 0) for spontaneous bleeds. Overall, 38% of subjects had zero bleeds. No bleeds were severe. Haemostatic efficacy was rated excellent or good for 90% of bleeds; 91% were treated with one or two infusions. In 8/14 subjects all target joints resolved. No subject developed FVIII inhibitors or persistent binding antibodies that affected safety or efficacy. No adverse reactions occurred. Conclusion: Twice-weekly prophylaxis with BAX 855 was safe and efficacious in paediatric PTPs with severe haemophilia A.
Haemophilia : the official journal of the World Federation of Hemophilia, 2016
BAX 855 is a pegylated full-length recombinant factor VIII (rFVIII) with an extended half-life, built on a licensed rFVIII (ADVATE(®) ). BAX 855 demonstrated efficacy and safety in prophylaxis and the treatment of bleeding episodes in previously treated patients (PTPs) with severe haemophilia A. This phase 3 surgery study evaluates the haemostatic efficacy and safety of BAX 855 for perioperative haemostasis in PTPs with severe haemophilia A undergoing surgery. Elective procedures were prospectively classified as major or minor. The dose and frequency of BAX 855 administered perioperatively were to be guided by each patient's pharmacokinetic profile for major procedures or BAX 855 incremental recovery for minor procedures. Haemostatic efficacy was evaluated using a predefined scale. Blood loss was compared to the expected average and maximum blood loss predicted preoperatively. A total of 15 male patients (aged 19-52 years) underwent 15 procedures (11 major and four minor). The o...
Haemophilia, 2010
Summary. Injected factor VIII (FVIII), the current treatment for haemophilia A, leads to major improvements in the quality of life and life expectancy of individuals with this disorder. However, because injected FVIII has a short half-life in vivo, this strategy has major limitations for highly demanding regimens (e.g. prophylaxis, immune tolerance induction, surgery). Newer formulations of longer-acting FVIII are presently under investigation. The use of low molecular weight polyethylene glycol (PEG)-containing liposomes as carriers for recombinant FVIII (rFVIII) results in the prolongation of haemostatic efficacy. Data from preclinical experiments in mice, early clinical evaluations, and pharmacokinetics and pharmacodynamics results indicate that an rFVIII pegylated liposomal formulation may provide potential clinical benefit to patients with severe haemophilia A by prolonging the protection from bleeding. In light of this potential clinical benefit, a multicentre, randomized, active-controlled, non-inferiority phase II trial with two parallel treatment arms and equal randomization after stratification for the presence or absence of target joints in patients and for ages ≥18 years vs. <18 years is currently being conducted. The study will test the hypothesis that rFVIII-Lip once-weekly prophylaxis is not inferior to rFVIII-water for injection thrice-weekly prophylaxis. A total of 250 patients will be enrolled with severe haemophilia A (<1% FVIII) on on-demand or secondary prophylaxis treatment and with documented bleeds or injections during the 6 months before study entry. Sixty-four centres in 14 different countries are involved in the study; recruitment is underway. In Italy, six centres have already included 15 patients (no screening failure). Eight of these patients have completed the run-in phase and have begun the home treatment. No unexpected serious adverse events have been reported thus far. Data emerging from this phase II study will help collect relevant data to overcome current limitations in haemophilia management by employing treatment with longer-acting rFVIII.
Factor VIII therapy for hemophilia A: current and future issues
Expert review of hematology, 2014
Hemophilia A is a congenital, recessive, X-linked bleeding disorder that is managed with infusions of plasma-derived or recombinant factor (F) VIII. The primary considerations in FVIII replacement therapy today are the: 1) immunogenicity of FVIII concentrates, 2) role of longer-acting FVIII products, 3) prophylactic use of FVIII in children and adults with severe hemophilia A, and 4) affordability and availability of FVIII products. Improving patient outcomes by increasing the use of FVIII prophylaxis, preventing or eliminating FVIII inhibitors, and expanding access to FVIII concentrates in developing countries are the major challenges confronting clinicians who care for patients with hemophilia A.
International Journal of Hematology, 2001
A multicenter and open-labeled clinical trial of human recombinant factor VIIa (rFVIIa) was conducted in Japanese patients with severe hemophilia A or B with inhibitors. The trial consisted of 2 parts. In study 1, the pharmacokinetics, pharmacodynamics, and safety of a single dose of 120 µg/kg of rFVIIa were investigated in 8 patients. In the subsequent study 2, the hemostatic effect and safety of rFVIIa were evaluated during a 24-week period in 10 patients. In study 1, the mean maximum FVII-coagulant activity (FVII:C) was found to occur after 10 minutes; activity then decreased rapidly and returned to the baseline within 24 hours after a single intravenous infusion of rFVIIa. The mean half-life of FVII:C was 3.5 hours. The activated partial thromboplastin time and prothrombin time in the patients were immediately shortened but returned to the baseline within 24 hours after dosing. In study 2, 86 µg/kg to 120 µg/kg of rFVIIa (mean, 97 µg/kg) was administered 1 to 85 times to 10 patients. A total of 58.0% (91/157) of bleeding episodes were treated excellently or effectively, with 5 (3.2%) ineffective episodes. There was no apparent trend in the relationship of the hemostatic effect with bleeding sites, mean dose, or number of injections. The efficacy rate, however, was significantly higher (90.0%) in bleeding episodes treated within 3 hours than in those treated at longer intervals (31.0%). No treatment-related adverse events were observed, and there was no evidence of antibody formation to rFVIIa. In conclusion, rFVIIa is an effective and well-tolerated option for treatment of bleeding episodes in hemophilia patients with inhibitors.
Haemophilia, 2009
BDDrFVIII is a B-domain deleted recombinant factor VIII (rFVIII) product for haemophilia A. Manufacture uniquely includes purification chromatography by synthetic-affinity ligand rather than murine-based monoclonal antibody, as well as an albumin-free cell culture process. BDDrFVIII was studied in 204 patients, including 62 subjects <16 years old, in two studies. A doubleblind, randomized, pharmacokinetic (PK) crossover study, utilizing a central laboratory assay (one-stage (OS)) for both drug potency assignment and plasma FVIII-activity measurements, demonstrated that BDDrFVIII was PK-equivalent to a fulllength rFVIII. Favourable efficacy and safety were observed: during defined routine prophylaxis in a patient population significant for preexisting target joints, nearly half (45.7%) of patients had no bleeding, and a low-annualized bleed rate (ABR) was achieved (median 1.9); 92.5% of haemorrhages (n = 187) required £2 infusions. Three subjects (1.5%, across both studies) developed de novo inhibitors (low-titre, transient), and the primary safety endpoint, based on a prospective Bayesian analysis, demonstrated the absence of neoantigenicity for BDDrFVIII. The PK-equivalence, based on central testing to align test and reference articles, and the novel Bayesian analysis of inhibitor safety in these investigations reflect robust experimental designs with relevance to future studies. This extensive dataset demonstrates the safety and efficacy of BDDrFVIII for haemophilia A.
Journal of Blood Medicine, 2016
rFVIIIFc (efraloctocog alfa, Eloctate ®) is an extended half-life (EHL) factor VIII licensed for use in patients with hemophilia A for prophylaxis and treatment of bleeding and surgical episodes. Pharmacokinetic studies in adults have shown a mean 1.5-fold increase in half-life compared to full-length factor VIII. When compared to adults, the half-life is decreased by 8% in adolescents between 12 and 17 years, by 18% in children 6 to ,12 years, and by 33% in children between the ages of 2 and ,6 years. There is a considerable interindividual variation in the prolongation of the half-life particularly in children and across the age groups, the range extending from no increase to a 2.5-fold increase. In addition to age, von willebrand factor (VWF) antigen level has demonstrated a significant impact on rFVIIIFc half-life, with higher VWF levels associated with greater prolongation of half-life. The pivotal and pediatric clinical trials have demonstrated the efficacy and safety of rFVIIIFc for use in regular prophylaxis and in management of bleeds and surgery. In these studies, just under half the participants showed a zero annualized bleed rate (ABR), and the median ABR (1.6 in the pivotal study for the individualized prophylaxis arm) showed a further decrease in the extension study. On average, the patients required fewer infusions (reduced by at least a third), and the mean weekly consumption seems to be in keeping with standard recombinant factor VIII. EHL rFVIIIFc has made decreased infusion frequency a possibility. However, the interindividual variability in dose and infusion frequency highlights the need for a personalized approach based on individual patient's half-life and/or response to treatment.
Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment
Blood, 2010
A long-acting factor VIII (FVIII) as a replacement therapy for hemophilia A would significantly improve treatment options for patients with hemophilia A. To develop a FVIII with an extended circulating half-life, but without a reduction in activity, we have engineered 23 FVIII variants with introduced surface-exposed cysteines to which a polyethylene glycol (PEG) polymer was specifically conjugated. Screening of variant expression level, PEGylation yield, and functional assay identified several conjugates retaining full in vitro coagulation activity and von Willebrand factor (VWF) binding.PEGylated FVIII variants exhibited improved pharmacokinetics in hemophilic mice and rabbits. In addition, pharmacokinetic studies in VWF knockout mice indicated that larger molecular weight PEG may substitute for VWF in protecting PEGylated FVIII from clearance in vivo. In bleeding models of hemophilic mice, PEGylated FVIII not only exhibited prolonged efficacy that is consistent with the improved ...